Intestine‐Targeted Controlled Hydrogen‐Releasing MgH₂ Microcapsules for Improving the Mitochondrial Metabolism of Inflammatory Bowel Disease

Abstract The development of efficient therapeutic agents with low side effects for inflammatory bowel disease management is a longstanding challenge. Recently, hydrogen molecule (H₂) is identified as an emerging spectrum‐wide, effective, and biosafe anti‐inflammatory agent, but intestine‐targeted H₂ delivery is still challenging. Here, an intestine‐targeted controlled hydrogen‐releasing microcapsule (MgH₂@EC@ES) is developed by confining abundant MgH₂ microparticles in the hydrophobic network of ethyl cellulose (EC) before being encapsulated with Eudragit S100 (ES) by a multistep microemulsion method. The pH‐responsive swelling feature of ES enables MgH₂@EC@ES microcapsules to escape from the stomach after oral administration and to hydrolytically produce a high amount of H₂ in the intestinal tract in a sustained way. High‐dose oral administration of MgH₂@EC@ES microcapsules exhibits a high outcome of colitis prevention, which is comparable to the first‐line drug 5‐aminosalicylic acid (5‐ASA) in the changes of body/spleen weights and disease activity and even better in the recovery of colon length and the improvement of histopathological change in the colon than 5‐ASA in a colitis mouse model. Mechanically, it is innovatively revealed that H₂ released from MgH₂@EC@ES microcapsules protects the complexes in the mitochondrial electron transfer chain from oxidative damage to enhance the energy metabolism of intestinal cells in support of mucosal restoration in colitis.